Thermodynamic stability of folded proteins against mutations

TL;DR

This paper analyzes the stability of folded proteins against mutations, deriving a theoretical framework that predicts a maximum size for stable single-domain proteins and their mutation insensitivity.

Contribution

It introduces a new theoretical model linking energy gap fluctuations to protein stability, providing bounds and estimates for mutation-induced instability.

Findings

Native states are unstable to mutations beyond a certain size scale.

Small proteins are predicted to be insensitive to random mutations.

Theoretical bounds and numerical estimates of instability are provided.

Abstract

By balancing the average energy gap with its typical change due to mutations for protein-like heteropolymers with M residues, we show that native states are unstable to mutations on a scale M* ~ (lambda/sigma_mu)^(1/zeta_s), where lambda is the dispersion in the interaction free energies and sigma_mu their typical change. Theoretical bounds and numerical estimates (based on complete enumeration on four lattices) of the instability exponent zeta_s are given. Our analysis suggests that a limiting size of single-domain proteins should exist, and leads to the prediction that small proteins are insensitive to random mutations.